Analysis of Tolerance and Behavioral/Physical Dependence during Chronic CB1 Agonist Treatment: Effects of CB1 Agonists, Antagonists, and Noncannabinoid Drugs

Behavioral studies of chronic CB 1 receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB 1 ligands as well as mechanistic commonalities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB 1 agonists [(6 aR ,10 aR )-3-(1-adamantyl)-6,6,9-trimethyl-6 a ,7,10,10 a -tetrahydrobenzo[ c ]chromen-1-ol (AM411), 9 β -(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R -(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3- de ]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), (R)-(+)-arachidonyl-19-hydroxy-29-propylamide (methanandamide)], CB 1 antagonists [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide (SR141716A), 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide (AM4113)], and dopamine (DA)–related [methamphetamine, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine hydrobromide (SKF82958), ( R )-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine hydrochloride (SCH23390), (6 aR )-5,6,6 a ,7-tetrahydro-6-propyl-4 H -dibenzo[ de,g ]quinoline-10,11-diol ( R -(−)-NPA), haloperidol] and opioid (morphine, naltrexone) drugs on scheduled-controlled responding under a 30-response fixed ratio schedule of stimulus-shock termination in squirrel monkeys were compared before and during chronic treatment with the long-acting CB 1 agonist AM411 (1.0 mg/kg per day, i.m.). Prechronic treatment with all drugs except naltrexone (1–10 mg/kg) produced dose-related decreases in responses rates. Dose-response re-determinations during chronic treatment revealed the following: 1) >250-fold (AM411, methanandamide) and >45-fold (AM4054, WIN55,212.2, Δ 9 -THC) rightward shifts in the ED 50 values for CB 1 agonists; 2) >100-fold and >20-fold leftward shifts in the ED 50 values for SR141716A and AM4113, respectively; and 3) approximately 4.8-fold and 10-fold rightward shifts in the ED 50 values for methamphetamine and the DA D 2 agonist R- (−)-NPA, respectively. Dose-response relationships for other DA-related and opioid drugs were unchanged by chronic CB 1 agonist treatment. Differences in the magnitude of tolerance among CB 1 agonists during chronic treatment may be indicative of differences in their pharmacological efficacy, whereas the enhanced sensitivity to behaviorally disruptive effects of CB 1 antagonists may provide evidence for CB 1 -related behavioral and/or physical dependence. Finally, the development of cross-tolerance to methamphetamine and R- (−)-NPA bolsters previous evidence of interplay between CB 1 and DA D 2 signaling mechanisms.